Pharmaceutical preparations are available that are based on the concomitant dosing of two or more active pharmaceutical ingredients (APIs). There have been various means to achieve this multiple API dosing including discrete dosage forms for each API, contained in a single package, multiple APIs in the one dosage form, multiple layers of different APIs in a compressed tablet.
The provision of packaging such as blister packs containing separate dosage forms for each API is not preferred as the person administering the API, including the patient per se, may confuse the different drugs with the consequent overdosing of one API whilst a second API is not dosed at all. EP 1003503 discloses a pharmaceutical composition containing amlodipine and atorvastatin that can be formulated in a single conventional dosage form or as part of a kit containing separate dosage forms for each API.
U.S. Pat. No. 6,417,191 discloses the combination of abacavir with lamivudine and optionally also zidovudine through simple admixture of these compounds and formulation with a suitable carrier. However, multiple APIs in a single dosage form can present problems of interaction of one API with another, an API with an excipient and/or different APIs requiring different release characteristics such as release-rate or the proximity of release in the gastrointestinal tract for example in the stomach, large or small intestine, or colon.
Many APIs exhibit some form of interaction with other APIs and/or with one or more of the many commonly used pharmaceutically acceptable excipients. One such classical interaction is the Maillard Reaction between an API containing a primary amine group and lactose, an extremely commonly used filler. This interaction forms a lactoside compound that may not exhibit any therapeutic effect, may cause the product to fail or worse still, the lactoside compound may be toxic and cause harmful side effects. This interaction with lactose can be seen with APIs such as amino acids, aminophylline, amphetamines and lisinopril.
Another well known interaction is that of some of the common proton pump inhibitor compounds and acidic excipients. APIs such as omeprazole, pantoprazole and lansoprazole are acid labile compounds that have been provided as enteric coated products to bypass the acidic environment of the stomach and release the API further down the GI tract where the pH is higher and the environment will not degrade the API before it can be absorbed. However, the most common enteric coating polymers are also acidic in nature. Therefore, these APIs contained in the core of the tablet, pellet or bead require additional protection from the acidic enteric coating polymer.
An example of how difficult it can be to formulate combined products with respect to excipient selection is shown wherein the API, olanzapine, has been found to interact with microcrystalline cellulose, a commonly used disintegrant and filler. This product is also marketed as a combined treatment with fluoxetine. As stated above, lactose interacts with primary amines and fluoxetine is a primary amine so there is potential for an interaction between these two ingredients. Thus a replacement filler would be required in order to formulate the fluoxetine into a tablet. Another common filler of choice is microcrystalline cellulose, however, due its interaction with the olanzapine, it cannot be used in a single dosage form containing both fluoxetine and olanzapine. Thus it becomes increasingly difficult to formulate more than one API into a single dosage form with acceptable excipients that do not interact with one or more of the APIs or other excipients.
Additional problems are associated with multi-layered compressed tablets as specialised compression equipment is required for preparation. Also, the separate layers may not eliminate the interactions between APIs or between API and excipient. Additional layers of an inert separating material can be used but this increases time, cost and complexity of the formulation of the compressed tablet. WO 2004/060355 discloses an example of a multi-layered tablet comprising a triptan in one layer and naproxen in another layer. There is optionally a separating layer between the two layers containing the APIs. WO 01/35941 discloses a combination of metformin hydrochloride and a thiazolidinedione (“glitazone”) whereby each API is dispersed in its own pharmaceutically acceptable carrier. In one preferred embodiment each of these separate compositions are contained in separate zones in a single dosage form, for example as compressed separate layers of a multi-layered tablet.
Alternatively, a core optionally containing an API, can be sprayed with a layer of API-containing, film-forming polymer. This can subsequently be sprayed with further layers comprising the same or different API and/or with some form of cosmetic, protective or rate-release control polymeric coating. Such cosmetic coatings can be a colour coat for cosmetic appeal, enhanced product presentation, taste-masking and product differentiation. Protective coatings can be used such as moisture barriers or protection against acidic environments. Rate-release control coatings can be pH solubility specific such as enteric coatings, pH insoluble coatings utilised with an osmotic pump system and a minute hole in the coating to control the release of the API or swellable polymers that control the rate of release of the API substance. Many such coatings are well known in the industry for each type of coating mentioned above. WO 2004/060355 also discloses an example whereby sumatriptan succinate is included in a film-coat that is applied to a core containing naproxen sodium. WO 2004/038428 discloses a formulation containing tramadol hydrochloride and acetaminophen to provide controlled-release of the API in the core and faster release of the API in the coating. WO 98/06385 discloses a similar coated core whereby both the core and the coating independently contain at least one API, different from the other.
Such spray layered products are time-consuming to manufacture and consequently exhibit a higher cost and complexity of manufacture. Additionally, the amount of API used in the coating solution must be larger than the amount required due to some of the coating solution passing through the tablet bed and being captured outside of the coating pan. The uniformity of dose is also difficult to achieve with the subsequent statistical coefficient of variation potentially being too large to be acceptable for release to market. U.S. Pat. Nos. 5,026,560 and 5,516,531 disclose non-pareil beads having a core coated with a binder and spraying powder containing a drug and low substituted hydroxypropylcellulose.
U.S. Pat. No. 6,015,577 discloses pellets of dipyridamole encapsulated with an acetylsalicylic acid tablet. The acetylsalicylic acid component is not free from acetic acid, which forms by cleavage of acetylsalicylic acid during storage, and acetic acid reacts with dipyridamole to form hygroscopic salts and esters and thereby degrade it. Therefore the tablet is coated with a coating suspension comprising sucrose, gum arabic and talc, the purpose being to separate the two APIs and so prevent degradation of dipyridamole over time in storage. U.S. Pat. Appl. 2006/0062856 discloses a controlled release formulation comprising particles of galantamine wherein the particles are coated by a release rate controlling membrane coating. It further discloses a dosage form wherein part of the galantamine is present as this controlled release formulation and another part is present in an immediate release form, preferably as mini-tablets. U.S. Pat. No. 6,514,531 discloses a controlled release dosage form to release zolpidem according to a biphasic in vitro dissolution profile. The two phases can be achieved by employing a controlled release dosage form comprising pellets spray-coated with a layer of 20% by mass of microcrystalline cellulose or a coated tablet and an immediate release dosage form comprising pellets or tablets incorporated into a larger tablet or capsule. This patent also discloses multilayer and multicoated tablets.
In addition to interactions between ingredients, it has also been seen that one API or one or more of the excipients used may interfere with the testing of one or both APIs in analytical testing methods. One example of this has been seen on High Performance Liquid Chromatography (HPLC) analysis where more than one API, an API and an excipient or an API and a related substance from another API co-elute at the same time thereby not allowing for the accurate quantitative determination of each separate substance. Similarly, excipient peaks can interfere and/or mask important API peaks in analytical techniques such as Ultra Performance Liquid Chromatography (UPLC), Infrared Spectroscopy (IR & FTIR), Near Infrared Spectroscopy (NIR), X-Ray Powder Diffractometry (XRPD) or Raman Spectroscopy. Similarly based interference can be seen with other spectroscopic or chromatographic analytical techniques for other APIs and formulations.
Thus there is a need for a dosage form to be developed that can overcome the difficulties of the prior art. More particularly, there is a need for a simple and cost-effective means to manufacture a dosage form which allows easy laboratory testing and that limits the potential of interactions of one API with further API(s) or with one or more of the excipients utilised in the formulation.